Chromatin states define tumour-specific T cell dysfunction and reprogramming

• Published in: Nature (London) 2017-05, Vol.545 (7655), p.452-456
• Main Authors: Philip, Mary, Fairchild, Lauren, Sun, Liping, Horste, Ellen L., Camara, Steven, Shakiba, Mojdeh, Scott, Andrew C., Viale, Agnes, Lauer, Peter, Merghoub, Taha, Hellmann, Matthew D., Wolchok, Jedd D., Leslie, Christina S., Schietinger, Andrea
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 38/39; 45/23; 45/91; 631/250/251; 631/250/580; 64/60; Animals; Cancer cells; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Chromatin; Chromatin - genetics; Chromatin - metabolism; Epigenesis, Genetic; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Humanities and Social Sciences; Humans; Immunologic Memory; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Male; Mice; multidisciplinary; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - therapy; Physiological aspects; Science; T cells; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature22367

Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1 hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1 hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability. Epigenetic programming of T cells in solid tumours from a functional to a dysfunctional state occurs in two phases, and only the first phase is reversible. Two phases of T cell dysfunction CD8 T cells are a critical component of the immune response against cancerous cells, but solid tumours often progress despite their presence. How these tumour-specific T cells become dysfunctional, and whether they can be reprogrammed, is not well understood. Andrea Schietinger and colleagues characterize the epigenetic profiles of exhausted dysfunctional T cells from solid tumours. They show that epigenetic programming from functional to dysfunctional T cells occurs in two phases, firstly through a plastic state and then through a fixed state, and that only the first phase is reversible. Understanding the epigenetic regulation of T cell dysfunction will be important when considering therapeutic reprogramming as part of cancer immunotherapies.